Triazolo{8 4,3-d{9 {8 1,4{9 benzodiazepine-3,6-diones

ABSTRACT

Compounds having the structure   WHEREIN R1 is hydrogen, alkyl, phenyl, or benzyl, R2 is hydrogen or alkyl, R3 is amino, alkylamino, or dialkylamino, R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio, and n is 2, 3, or 4 are useful as anti-inflammatory agents.

United States Patent [1 1 Vogt et al.

[ 5 TRIAZOLO[4,3-D][1,4]BENZODIAZEPINE- 3,6-DIONES [75] Inventors: B. Richard Vogt, Yardley, Pa.; Peter C. Wade, Pennington, NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Mar. 4, 1974 [21 Appl. No.: 447,719

Primary Examiner-Henry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Donald J. Barrack [451 July 15,1975

[57] ABSTRACT Compounds having the structure (CH2) n 3 wherein R is hydrogen, alkyl, phenyl, or benzyl, R is hydrogen or alkyl, R is amino, alkylamino, or dialkylamino, R is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio, and n is 2, 3, or 4 are useful as anti-inflammatory agents.

12 Claims, No Drawings 1 TIRAZOLO[3,4-D][l ,4]BENZODIAZEPINE-3,6-

DIONES SUMMARY OF THE INVENTION Compounds having the structure and the pharmaceutically acceptable acid-addition salts thereof, are useful anti-inflammatory agents.

In formula I, and throughout the specification, the symbols are as defined below:

R can be hydrogen, alkyl, phenyl, or benzyl;

R can be hydrogen or alkyl;

R; can be amino, alkylamino, or dialkylamino;

R, can be hydrogen, halogen (preferably fluorine,

chlorine or bromine), nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio; and

n is 2, 3, or 4.

The term alkyl as used throughout the specification, either by itself or as part of a larger group, refers to both straight and branched chain alkyl groups containing l, 2, 3, or 4 carbon atoms.

The term alkoxy, as used throughout the specification, refers to a group of the formula Y-O, wherein Y is alkyl as defined above.

The term halogen, as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention are produced from compounds having the formula II R wherein R can be halogen (preferably bromine or chlorine), sulfhydryl, alkoxy, alkylthio, or phenylalkylthio and R can be alkyl, phenyl, or benzyl. The compounds of formula II are known; see for example US. Pat. No. 3,414,563 and Swiss Pat. No. 485,742.

Reaction of a benzodiazepine of formula II with an alkyl carbazate having the formula wherein Z is alkyl, yields a compound having the structure III HN-N-C-OZ H 0 The reaction can be run without a solvent, or in a nonreacting organic solvent, at a temperature of from about 50C to 250C for about 5 minutes to 24 hours, preferably from about C to C for about 30 minutes to 6 hours. The benzodiazepine of formula II, and the alkyl carbazate are reacted in approximately a 1:1 molar ratio. Heating a compound of formula III at an elevated temperature, e.g., 80C to 200C, preferably 100C to 180C, yields a compound having the structure The compounds of formula IV are novel intermediates, and as such, they constitute a part of this invention.

In order to obtain the triazolobenzodiazepines of formula I, a triazolobenzodiazepine of formula IV is reacted with an appropriate base,e.g., thallous ethoxide,

The salt of formula V is subsequently reacted with a compound having the formula R (CH ),,X, wherein X can be chlorine, bromine, iodine, alkylsulfonate (e.g., methanesulfonate) or arylsulfonate (e.g., toluenesulfonate), to obtain a compound having the structure l N \N l (CH 2 R 3 The reaction of a triazolobenzodiazepine of formula IV with thallous ethoxide is run in a non-reactive polar solvent, e.g., dimethylformamide, at a temperature of from about 0C to 180C, preferably at room temperature to 80C, for a period of about 1 minute to 5 hours, preferably for. l0 minutes to 1 hour. The reaction of a salt of formula V with a compound of the structure R (CI-I ),,X is run at about 50C to 200C for a period of about 30 minutes to 72 hours, preferably at 80C to 140C for 2 to 24 hours.

Alternatively, the compounds of formula VI can be prepared by first reacting a salt, such as the salt of formula V, with a compound having the formula VII III R The reaction of a salt of formula V with a compound having the formula I-IO(CI-I ),,--X is run at about 50C to 200C for a period of about 30 minutes to 72 hours, preferably at 80C to 140 C for 2 to 24 hours. The compounds of formula VIII are novel intermediates, and as such, they constitute-a part of this invention.

The compounds of formula VIII can be converted to the corresponding compounds of formula VI using procedures well known in the art. The proton of the hydroxyl group in the compounds of formula VIII is first converted to a leaving group, e.g., by reacting the compounds with an alkyl (or aryl) sulfonyl halide in the presence of a nonreacting organic base. The resulting intermediate can then be converted to a compound of formula VI by reacting it with ammonia, an alkylamine, or a dialkylamine. This reaction can be carried out in an organic solvent, e.g., toluene, at a temperature of from 25C to 200C for minutes to 24 hours, preferably at 80C to 150C for 1 hour to 5 hours.

Reduction of triazolobenzodiazepines of formula VI, wherein R is benzyl, to yield compounds having the structure can be accomplished by reacting the compound with hydrogen under pressure in the presence of a catalyst, e. g., palladium or Raney nickel, or by reacting the compound with anhydrous liquid hydrofluoric acid.

, Compounds of formula I wherein R is hydrogen are preferred.

Compounds of formula I wherein R is dialkylamino are preferred.

Compounds of formula I wherein n is 2 or 3 are preferred.

Compounds of formula I wherein R is in the 9 or 10- position are preferred, and those wherein R is in the l0-position are particularly preferred. Compounds of formula I wherein R is halogen or trifluoromethyl are preferred, chlorine being the most preferred halogen.

The triazolobenzodiazepines of formula I form pharmaceutically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts, in addition to having the useful pharmacological activity of the corresponding free base, frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with. a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate acid. Illustratiive are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The triazolobenzodiazepines of formula I, and the pharmaceutically acceptableacid-addition salts of the compounds, are useful in treating inflammation in mammalian species, e.g., rats, dogs, cats, monkeys, etc. Joint tenderness and stiffness (in condiditions such as rheumatoid arthritis) are relieved by the above described compounds.

"I'he compounds of this invention are formulated for use as anti-inflammatory agents according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs, or powders, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. The compounds of this invention may be administered in amounts of 100 mg/kg/day to 2 g/70kg/day, preferably mg/70kg/day to I g/70/day.

The following examples are specifiic embodiments of this invention.

5 EXAMPLE 1 l-Chloro-2-[2-(dimethylamino)ethyl]-2,7-dihydro-7- methyl-3H-s-triazolo[4,3-d][ 1,4]benzodiazepine- 3,6(H)-dione, hydrochloride (1:1)

A. -Chloro-2,7-dihydro-7-methyl-3H-s-triazolo 4,3-d 1 ,4]benzodiazepine-3,6( 5H )-dione 5 ,7-Dichlorol ,3-dihydrol-methyl-Zl-ll ,4- benzodiazepin-2-one (50 g) and ethylcarbazate (43 g) are refluxed in 2,000 ml of toluene for 4 hours. The toluene is decanted from the insoluble mixture and removed under vacuum, producing a white powder which is freed from the accompanying viscous material by stirring with acetonitrile. The white powder is insoluble and is filtered off; the filtrate is saved.

The residue from the original reaction mixture is refluxed for 4 hours in dioxane. The solvent is then removed under vacuum leaving a white powder which is stirred with acetoniitrile to remove viscous impurities. This mixture is filtered, the white powder combined with the powder obtained previously (total 45 g) and recrystallized from 50% methanoldioxane to yield the title compound, melting point 268-269C.

Both acetonitrile filtrates are combined, stripped and heated at about 100C for 2 days. This process yields another 5.5 g of product.

Anal. Calcd for C H ClN O C, 49.92; H, 3,42; N, 21.17; Cl, 13.40. Found: C, 49,85; H, 3.44; N, 21.20; Cl, 13.32.

10-Chloro'2-[2-(dimethylamino)ethyl]-2,7-dihydro-7- methyl-3H-s-triazolo 4,3-d][ 1,4]benzodiazepine- 3,6(5H)-dione, hydrochloride (1:1

10-Chloro-2,7-dihydro-7-methyl-3-H-s-triazolo[4,3- d]-[l,4]benzodiazepine-3,6(5H)-dione (7.92 g) is suspended in 120 ml of tetrahydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes and the mixture is then filtered. The filter cake is washed by stirring as a slurry with ether, aand filtered to yield 13.5 g of the thallium salt.

2-(Dimethylamino)ethyl chloride (1.5 equivalents) is added to a refluxing suspension of the thallium salt in 600 ml of toluene. After 2 hours of reflux, another equal amount of 2'-(dimethylamino)ethyl chloride is added and the refluxing is continued for 5 hours.

The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thal lium salts. The infusorial earth is washed by stirring in benzene and filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 X 4.5 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed Example Column 1 diazepin-2-one 4 S-chloro-l 3-dihydrol -methyl-7 nitro2Hl ,4-benzodiazepin-2-one 5 5-chloro-7-ethylthio-1 ,3-dihydrol-methyl-2H 1 ,4-benzodiazepin-2-one under vacuum to yield 7.5 g of product. Recrystallization from ethyl acetate and then from hexane gives a pure product.

A sample (3.5 g) of the product is dissolved in a mixture of methanol and ether (just sufficient methanol to achieve solution), and slightly more than one equivalent of HCl (ethereal) is added. The precipitate is filtered off and further purified by dissolving it in hot methanol, followed by reprecipitation with ether, to give 3.6 g of the title compound, which is dried under vacuum at 140C overnight. The product has a melting point of 284285.5C. Anal. Calcd. for C H Cl N O C, 48,40; H, 5.15; N, 18.81; Cl, 19.05.

Found: C, 48.14; H, 5.42; N, 18.60; Cl, 18.78.

EXAMPLE 2 10-Chloro-2- 3'(dimethylamino )propyl -2,7-dihydro- 7-methyl-3H-s-triazolo[4,3-d][ 1 ,4]benzodiazepine- 3,6(5H)-dione 10-Chloro-2 ,7-dihydro-7-methyl-3H-s-triazolo 4,3 d]-[l,4]benzodiazepine-3,6(5H)-dione (2.64 g, prepared as described in Example 1A) is dissolved in 40 ml of'dimethylformamide at C. Thallous ethoxide (2.49 g) is added dropwise to the solution while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes, the mixture is cooled to 25C, and 200 ml of ether is added. The resulting precipitate is filtered off and dried at 25C under vacuum for 4 hours to yield 4.5 g of the thallium salt.

3-(Dimethylamino)propy l chloride (1.5 equivalents) is added to a refluxing solution of the thallium salt prepared above in 150 ml of toluene. After 3 hours of reflux, an equal amount of 3-(dimethylamino)propyl chloride isadded and the refluxing is continued for 5 hours.

The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 X 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield 2.6 g of product. Recrystallization from ethyl acetate yields the title compound, which is dried for 2 hours at C under vacuum. The title compound has a melting point of 178l79C.

Anal. Calcd. for C H ClN O C, 54.95; H, 5.76; N, 20.02; C], 10.14. Found: C, 54,72; H, 6.00; N, 20.02; C1, 10.06.

EXAMPLE 3 13 Following the procedure of Example 1, but substituting the compounds indicated in column 1 below for 5,7- dichloro- 1 ,3-dihydro- 1 -methyl-2H- 1 ,4-benzodiazepin- 2-one, the compounds indicated in column 11 are obtained.

Column 11 7-benzyl-2-[2-(dimethylamino)ethyl]- 2,7-dihydro10-(trifluoromethyl)-3H- s-triazolo[4,3-d] 1,4]benzodiazepine- 3,6(5H)-dione, hydrochloride 1,4]benzodiazepine-3,6(5l-l)-dione, hydrochloride 2-[2-(dimethylamino)ethyl]-IO-ethylthio- 2,7-dihydro-7-methyl-3H-s-triazolo[4,3d]- 1,4]benzodiazepine-3,6(5H)-dione, hydrochloride Example Column I Column 11 6 5-chlorol ,3-dihydrol ,7-dimethyl- 2H- l ,4-benzodiazepin-2-one 7 5-chloro-1,3-dimethyl-l,3-dihydro- 7-( trifluoromethyl)-2H-l ,4-benzodiazepin-Z-one 8 8-bromo-5-ethoxyl ,S-dihydrol phenyl-ZH-l ,4-benzodiazepin-2-one 9 l-benzylJ-cyanol ,3-dihydro-5 (methylthio )-2H-l ,4-benzodiazepin- 2-one l l-benzyl-7-chloro-l ,3-dihydro-2H- l ,4-benzodiazepin-2-onc-5-thione l l -chloro-7-ethyll ,3-dihydrol phenyl-ZH- l ,4-benzodiazepin-2-one l2 S-chlorol -ethyll ,S-dihydro-ZH- l ,4-benzodiazepin-2-one l3 5-chlorol ,3-clihydro-7-(methoxy)- l-methyl-ZH- l ,4-benzodiazepin-2-one 2-[2-(dimethylamino)ethyl]-2,7dihydro- 7,10-dimethyl-3H-s-triazolo[4,3-d1 1,4]- benzodiazepine-3,6(5H)dione, hydrochloride 2-[ 2-( dimethylamino)ethyl]-2,7-dihydro- 5,7-dimethyll 0-( trifluoromethyl)-3 H-striazolo[4,3-d] 1,4]benzodiazepine-3,6- (5H)-dione, hydrochloride 9-bromo-2-[2-(dimethylamino)ethyl]-2,7- dihydro-7-phenyl-3H-s-triazolo[4,3-d1 1,4]-

benzodiazepine-3,6(5H )-dione, hydrochloride.

hydrochloride EXAMPLES l4 16 Following the procedure of Example 2, but substituting the compounds indicated in column I below for 3- (dimethylamino)propyl chloride, the compounds indicated in column II are obtained.

Example Column I Column II and stirred for 1 hour at room temperature. The solution is diluted with 300 ml of ether, and the precipitated salt is filtered off.

3-(Dimethylamino)propyl chloride (1.5 equivalents) is added to a refluxing solution of the thallium salt pre- 14 3-aminopropyl chloride 2-[ 3-(amino )propyl]- l 0-chloro-2,7-dihydro- 7-methyl-3H-s-triazolo[4,3-d] 1,4]benzodiazepine-3,6(5I-I)-dione l 5 3-( ethylamino )propyl chloride lO-chloro-2-[ B-(ethylamino )propyl ]-2,7-

l6 4-( diisopropylamino)butyl chloride l0-chloro-2-[4-(diisopropylamino)butyl]2,7- dihydro-7-methyl-3H-s-triazoldL4,3-d] 1,4]-

benzodiazepine-3,6(5H)-dione EXAMPLE l7 l0-Chloro-2-[ 3-(dimethylamino )propyl ]-2,7-dihydro- 3H-s-triazolo[4,3-d 1,4]benzodiazepine-3 ,6( 5H dione 7-Benzyll O-chloro-2,7-dihydro-3H-s-triazolo[4,3-d 1,4]benzodiazepine-3,6(5I-I)-dione 7-Benzyll 0-chloro-2-[ 3-(dimethylamino )propyl -2,7- dihydro-3H-s-triazolo[4,3-d][ l,4]benzodiazepine-3,6-

(5l-I)-dione 7-Benzyll 0-chloro-2,7-dihydro-3I-I-s-triazolo[4,3- d]-[1,4]benzodiazepine3,6(5I-I)-dione (0.02 mole) is dissolved in 100 ml of dimethylformamide at 70C. Thallous ethoxide (0.02 mole) is added to the solution pared above in ml of toluene. After 3 hours of reflux, an equal amount of 3-(dimethylamino)propyl chloride is added and the refluxing is continued f0r l4 hours.

The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 X 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield 7-benzyl-l0-chloro-2-[3- (dimethylamino)propyl]-2,7-dihydro-3H-striazolo[4,3-d][ 1 ,4]benzodiazepine-3,6(SID-dione.

C. l0-Chloro-2-[ 3-(dimethylamino )propyl -2,7-dihydro- 3H-s-triaz0lo[4,3-d][ 1,4]benzodiazepine-3 ,6( 5H)- dione 7-Benzyl- 1 0-chloro-2-[ 3-(dimethylamino)propyl]-2,7- dihydro-3H-s-triazolo[ 4,3-d][ l ,4]benzodiazepine- 3,6(5H)-dione (0.01 mole) is hydrogenated at 60C in 300 ml of acetic acid contining 0.3 g of pre-reduced Raney nickel. The initial hydrogen pressure is 60 p.s.i. The reduction is stopped after 0.01 mole of hydrogen is absorbed, the catalyst is filtered off, and the solvent is evaporated. The residue is stirred with water and 10-ch1oro-2-[3-(dimethylamino)-propyl]-2,7-dihydro- 3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(51-1)- dione is filtered off and dried.

EXAMPLES 18 20 Following the procedure of Example 17, but substituting the compound indicated in column 1 below for l-benzyl- ,7-dichlorol ,3-dihydro-2H-l ,4 benzodiazepin-Z-one and the compound indicated in column 11 below for 3-(dimethylamino)propy1 chloride, the compound indicated in column 111 is obtained.

Example Column 1 Column 11 18 l-benzyl-S-chloro-l ,3-dihydro- 7-( methoxy)-2H- l ,4-benzodiazepin- 2-one 2 1+1 ,4-benzodiazepin-2-one chloride 2-aminoethyl chloride 3-( methylamino )propyl chloride 2-( isobutylamino)ethyl C. 10-Chloro-2,7-dihydro-2-[ 3( isopropylamino )propyl 7-methyl-3l-l-s-triazolo[4,3-d][ 1,4]benzodiazepine- 3,6-(5H )-dione 10-Chloro-2,7-dihydro-7-methyl-2-[ 3-(p- Column 111 2-[2-(amino)ethy1]-2,7- dihydrol O-(methoxy )-3H-striazolo[4,3-d] 1,4]benzodiazepine-3,6(5H)-dione 2 ,7-dihydro-5 l O-dimethyl- 2-[ 3-(methylamino)propyl]- 3Hs-triazolo(4,3-d] 1,4]- benzodiazepine-3,6(5H)-dione 2,7-dihydro-2-[2-(isobutylaminolethyl]-3H-s-triazolo- [4,3-d] 1,4]benzodiazepine- 3,6(5H)-dione EXAMPLE 21 10-Chloro-2,7-dihydro-2-[ 3-(isopropylamino)propyl]- 7-methy1-3l-1-s-triazolo[4,3-d][1,4]benzodiazepine- 3,6(5H)-dione A. 10-Ch1oro-2,7-dihydro-2-(3-hydroxypropyl)-7-methyl- 3H-s-triazolo[4,3-d][ 1,4]benzodiazepine-3,6(5H)- dione 10-Chloro-2,7-dihydro-7-methyl-3H-s-triazolo[4,3- d]-[1,4]benzodiazepine-3,6(5H)-dione (7.92 g, prepared as described in Example 1A) is suspended in 120 ml of tetrahydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes and the mixture is then filtered to yield 13.5 g of the thallium salt.

To a stirring, refluxing suspension of 3 g of the thallium salt in toluene is added 3 ml of l-chloro-3- hydroxypropane. After refluxing for 72 hours, another 3 ml of the chloro alcohol is added and heating is continued for another 24 hours. The solution is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and then filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 X 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield 1.3 g of a product. Recrystallization from ethyl acetate, and dry ing under vacuum for 2 hours at 100C, gives the title compound, melting point l71-172C.

Anal. Calcd. for C H C1N O C, 52.10; H, 4.68; N, 17.36; Cl, 10.99. Found: C, 51.88; H, 4.75; N, 17.38; Cl, 11.10.

B. 10-Chloro-2,7-dihydro-7-methyl-2-[ 3-( ptoluenesulfonyloxy )propyl]-3H-s-triazolo[4,3-d][ 1 ,4 1- benzodiazepine-3,6(5H)-dione toluenesulfonyloxy)propyl]-3H-s-triazolo[4,3- d][1,4]benzodiazepine-3,6(5l-l)-dione and isopropylamine (0.1 mole) are refluxed in 600 m1 of toluene for 3 hours. The reaction mixture is cooled to 25C and the resulting precipitate is filtered off. The product is extracted from the toluene filtrate into 10% hydrochloric acid. The acid solution is made basic with 10% sodium bicarbonate and the product is extracted into chloroform. The solvent is removed under vacuum, and the residue is recrystallized from ethanol and dried under vacuum at 40C for 3 hours to give the title compound.

What is claimed is:

1. A compound having the formula or a pharmaceutically acceptable acid-addition salt thereof, wherein R is hydrogen, alkyl, phenyl or benzyl; R is hydrogen or alkyl; R; is amino, alkylamino or dialkylamino; R is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy or alkylthio; and n is 2, 3 or 4; wherein alkyl is alkyl of 1 to 4 carbon atoms and alkoxy is alkoxy of 1 to 4 carbon atoms.

2. A compound in accordance with claim 1 wherein R is amino.

3. A compound in accordance with claim 1 wherein R is alkylamino.

4. A compound in accordance with claim 1 wherein R is dialkylamino.

5. A compound in accordance with claim 1 wherein (0.05 mole) hydrochlo- Z Z Y o wherein R is hydrogen or alkyl; R, is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy or alkylthio; and R is alkyl, phenyl or benzyl; and wherein alkyl is alkyl of l to 4 carbon atoms and alkoxy is alk- 5 oxy of l to 4 carbon atoms.

11. A compound having the formula 6 l N 0 4 X R 2 N v l N wherein R is hydrogen or alkyl; R is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy or alkylthio; R is alkyl, phenyl or benzyl; and n is 2, 3 or 4;: and wherein alkyl is alkyl of l to 4 carbon atoms and alkoxy is alkoxy of l to 4 carbon atoms.

12. The compound in accordance with claim 11 having the name hydroxypropyl)-7-methyl-3H-s-triazolo[4,3-

d][ l,4]benzodiazepine-3,6(5H)-dione.

lO-chloro-2,7-dihydro-2-( 3- 

1. A COMPOUND HAVING THE FORMULA
 2. A compound in accordance with claim 1 wherein R3 is amino.
 3. A compound in accordance with claim 1 wherein R3 is alkylamino.
 4. A compound in accordance with claim 1 wherein R3 is dialkylamino.
 5. A compOund in accordance with claim 1 wherein R1 is alkyl, phenyl or benzyl.
 6. A compound in accordance with claim 1 wherein R1 is hydrogen.
 7. A compound in accordance with claim 1 wherein R2 is hydrogen.
 8. The compound in accordance with claim 1 having the name 10-chloro-2-(2-(dimethylamino)ethyl)-2,7-dihydro-7-methyl-3H-s-triazolo(4,3 -d)(1,4)benzodiazepine-3,6-(5H)-dione, hydrochloride.
 9. The compound in accordance with claim 1 having the name 10-chloro-2-(3-(dimethylamino)propyl)-2,7-dihydro-7-methyl-3H-s-triazolo(4,3-d)(1,4)benzodiazepine-3,6(5H)-dione.
 10. A compound having the formula
 11. A compound having the formula
 12. The compound in accordance with claim 11 having the name 10-chloro-2,7-dihydro-2-(3-hydroxypropyl)-7-methyl-3H-s-triazolo(4, 3-d)(1,4)benzodiazepine-3,6(5H)-dione. 